Cancers are a major cause of mortality. High grade gliomas are particularly devastating malignant tumours, for which there is currently no effective cure and for which the outcome is normally fatal. Certain treatments can prolong survival, but they do not cure the cancer.
Malignant glioma is a cancerous tumour that is confined to the brain and only rarely spreads further. The current standard therapy involves surgically removing the solid tumour mass and initiating radiotherapy and/or chemotherapy. Even when the solid tumour mass is being removed, precancerous or isolated cancerous cells can exist in the brain. In the majority of these patients, a new tumour grows and a repeat operation is frequently required. Currently most available cancer medicines are generally very toxic and many do not readily reach the brain tumour. They often cause severe side effects that can reduce the patient's quality of life significantly.
EP1135513 relates to an adenovirus-based gene therapy. The therapy involves the use of adenovirus having a functional thymidine kinase gene, for the treatment of a brain tumour cavity resulting from tumour resection. Following standard surgery to remove the solid tumour mass, the adenovirus is injected through the wall of the cavity left behind by the surgical removal of the solid tumour, in to the surrounding healthy brain tissue. This causes the healthy cells in the wall of the cavity to express Herpes simplex virus thymidine kinase (HSV-tk). The drug ganciclovir is then given to the patient. HSV-tk and ganciclovir react together to produce a substance which destroys cells when they try to divide. This prevents another tumour growing around the site of the removal of the original tumour.
The therapy “Cerepro”, developed by the Applicant, is based on the above principal. It has been shown in clinical trials to have therapeutic benefits for patients with high grade glioma.
Previous evidence and current general expectation is that pre-existing antibodies that have the ability to neutralise adenovirus infectivity, will inhibit the therapeutic activity of medicinal adenoviral gene therapy vectors. This is because it is believed that they will inhibit their ability to infect tissue, and therefore their ability to effect expression of the transgene. Evidence for this may be found in King et al, 2008, which describes treatment with an Ad-HSV-tk vector and ganciclovir, in a rat glioma model. It was found that the treatment induced tumour regression and prolonged survival, but was ineffective in rats that were pre-immunised with the vector. The authors proposed that less immunogenic “gutless” adenoviral vectors would be required for clinical efficacy in patients that had pre-existing immunity to the adenovirus.
Further, in Barcia et al., 2007, it was found that prolonged expression of a marker gene from an adenoviral vector injected into the mouse brain was prevented by pre-immunising the mouse with adenovirus. Prolonged expression could be achieved in pre-immunised mice if a less immunogenic “gutless” adenoviral vector was used. Additionally, in Brouwer E et al., 2007, the authors proposed that adenoviral vectors based on Ad35 would be clinically preferable to Ad5-based vectors for treatment of malignant glioma because of the inhibitory effect of pre-existing immunity to the Ad5 vectors.
Okada et al 2009, propose using cytokines to maximise specific anti-tumour immunity when using an Ad-HSV-tk vector with ganciclovir. When the group tested various immunostimulatory therapies in a rat model of glioma, only fms-like tyrosine kinase ligand (FIt3L) was effective delivered in combination with Ad-HSV-tk, whereas CD40L and IL-12 were not effective. The immunosuppressor cyclosporine A inhibited the efficacy. It is important to realise that the experiments were carried out in a rat model, which is not an accurate indicator of therapeutic effect in humans. Also, the treatment is based on using tumour antigens.